Vesicular zinc modulates neuronal excitability through its effects on synaptic and intrinsic properties. In the dorsal cochlear nucleus (DCN), an auditory brainstem nucleus, zinc containing terminals have been identified. However, the neuromodulatory role of synaptic zinc in the DCN or in any other auditory circuit remains unknown. The long term goal of this proposal is to unravel the neuromodulatory role of the synaptic zinc in the DCN. The central hypothesis is that synaptic zinc controls the excitability of the DCN circuit through activity- dependent modulation of the intrinsic and synaptic properties of the principal cells. In Aim 1, the role of synaptically released zinc on intrinsic properties and firing patterns of DCN principal neurons will be determined. For this purpose the membrane ionic conductance's modulated by synaptic Zn2+ will be identified using electrophysiological approaches. In Aim 2, the role of synaptically released zinc on synaptic properties of DCN principal neurons will be determined. To accomplish this, the cellular mechanism involved in the Zn2+-mediated modulation of endocannabinoid signaling in DCN principal neurons will be identified. We will employ electrophysiological, immunohistochemicals, and Ca2+ imaging techniques. These studies will provide a framework to understand the role of zinc in auditory processing. PUBLIC HEALTH RELEVANCE: The study of the role of synaptically-released Zn2+ on the synaptic and intrinsic properties of dorsal cochlear nucleus neurons is expected to help in elucidating the role of Zn2+ in auditory circuits. Lack of synaptic zinc has been shown to produce hyperexcitability in different areas of the CNS (Cole et al;2000;Williamson and Spencer, 1995). Therefore, our results are expected to reveal mechanisms underlying hyperexcitability in the DCN. Given that previous studies have revealed DCN hyperexcitability in animal models with behavioral evidence of tinnitus, the conclusions of our study may be relevant for the observed tinnitus-related hyperexcitability.